ErbB2-ErbB3 Signaling

The ErbB family of transmembrane RTKs play an important role in the pathogenesis of many cancers. The family comprises of four members: EGFR/ErbB1, ErbB2, ErbB3, and ErbB4. ErbB2 (also called Her2) and ErbB3 are closely related to EGFR/ErbB1. Unlike EGFR, ErbB2 is a ligand-less receptor, while ErbB3 lacks tyrosine kinase activity. Hence, both ErbB2 and ErbB3 are active only in the context of ErbB heterodimers. ErbB2-ErbB3 heterodimers which are driven by Neuregulin (NRG) ligands, are the most prevalent and potent complexes in terms of cell growth and transformation. The basis for the potency of signaling by the ligand activated ErbB2-ErbB3 heterodimer lies in the fact that this dimer has the capacity to signal both through the Ras-ERK pathway, for proliferation, and through the PI3K/AKT/PKB pathway, for survival. In addition, this receptor complex evades downregulation mechanisms, leading to prolonged signaling.Upon ligand activation, the receptor dimer binds GRB2, either directly via a phospho-tyrosine containing consensus site, or indirectly via its interaction with SHC. This is followed by activation downstream of the Ras/Raf/MEK/ERK pathway. ERK activates a number of transcription factors such as Sp1, Elk-1, c-Jun and c-Myc. Other important pathways include the JAK/STAT and the PI3K/AKT pathways. The anti-apoptotic function of the PI3K/AKT pathway is mediated through the inhibition of pro-apoptotic proteins BAD, GSK3 and the transcription factor FKHR-L1. Another major player, acting downstream of ErbB2-ErbB3 is Cyclin-D1, which plays a role in cell cycle progression. The outcome of activation of these different signaling pathways depends on the cellular context, and can vary from proliferation to differentiation, migration, even induction of apoptosis.